Antimycotic gel with high active substance release

ABSTRACT

A pharmaceutical preparation comprising a hydrophilic gel-forming agent, water and a compound of the formula I                  
 
is suitable for the treatment and prophylaxis of dermatomycoses.

The present invention relates to a topically applicable antimycoticpreparation having a high active compound release in the form of a gelpreparation which contains at least one antimycotic substance from thehydroxypyridone class and at least one hydrophilic gel-forming agent.

For the topical treatment of mycoses, especially mycoses of the skin,various preparation forms of hydroxypyridone derivatives such assolutions, ointments and powders are already known. Optimum treatment ofdermatomycoses, however, using the preparation forms ofhydroxy-pyridones known until now is not unrestrictedly possible for themost diverse reasons.

Topically applicable liquid preparations in general include clearaqueous or aqueous-alcoholic solutions. They are either painted onto theskin surface or used for washing or baths. In particular, they are usedin any skin regions which are covered by dense hair growth, sinceointments or powders are not suitable for these areas. Moreover, theyare used in those skin areas for which other pharmaceutical forms arenot willingly used for cosmetic reasons, e.g. on the face or on highlymobile body sites (e.g. elbows, knee etc.).

The release rate of the active compound from solutions is generallyhigh, since after application by evaporation of the vehicleconstituents, a high concentration gradient between the preparation andthe skin results, which in the end leads to a high absorption of activecompound through the skin and thus to a high efficacy.

With respect to their applicational properties, solutions, however, areas less favorable, since on account of their liquid aggregate state theycan only be handled with difficulty, in particular on the face, and aspecific application to restricted skin areas is not possible.

Ointments or semisolid pharmaceutical preparation forms areadministration forms which in general are spreadable in the temperaturerange between room temperature and skin temperature and thereby can bedifferentiated from the liquid administration forms and those with solidcharacter. Based on the substance characteristics of the skin vehiclesubstances, ointments are in general understood as meaning anhydrousfatty bases or emulsions consisting of an oily and aqueous phase, whichare stabilized by an emulsifier.

On account of their semisolid consistency, ointment preparations—incontrast to solutions—can be applied very specifically to restrictedskin areas. Owing to the content of fatty constituents, however, therelease of the lipophilic hydroxypyrrolidone derivatives from theointment constituents is highly restricted. The success of treatmentafter ointment application is furthermore adversely affected by the factthat ointments do not usually leave behind a wipe-resistant film on theskin. On contact with the clothing or bed linen, the product applied canthus be easily removed again and is thus no longer available forsuccessful therapy.

Powder preparations are primarily used for the adsorption of increasedsecretion and keeping the skin dry; a point which, in particular in thetreatment of dermatomycoses, plays an important part. For practicalreasons, the application of powder preparations is almost exclusivelyrestricted to the treatment of mycosis pedis.

It has now been found that gel formulations of hydroxypyridonederivatives, which contain solvents and hydrophilic gel-forming agentsand also customary formulation auxiliaries, make possible a high releaseof the active compound and thus an improved action due to theachievement of high concentrations of the active compound in the skin.The preparations according to the invention can furthermore be appliedto the affected skin areas easily and specifically on account of theirsemisolid consistency, and moreover, exhibit the desired drying-outeffect, particularly in the treatment of mycosis pedis.

The invention therefore relates to a pharmaceutical preparationcomprising a hydrophilic gel-forming agent, water and a compound of theformula I

or a physiologically tolerable salt of the compound of the formula I,where R¹, R² and R³, which are identical or different, are a hydrogenatom or alkyl having 1 to 4 carbon atoms, and R⁴ is a saturatedhydrocarbon radical having 6 to 9 carbon atoms.

A preferred pharmaceutical preparation is one where

-   R⁴ is a saturated hydrocarbon having 6 to 9 carbon atoms, one of the    radicals R¹ and R³ is a hydrogen atom and the other is a hydrogen    atom, methyl or ethyl and R² is an alkyl radical having 1 or 2    carbon atoms.

A particularly preferred pharmaceutical preparation is one wherein thecompound of the formula I contains a cyclic radical in the position R⁴.

Furthermore preferred is a pharmaceutical preparation wherein R⁴ is acyclohexyl radical or —CH₂—CH(CH₃)—CH₂—C(CH₃)₃.

The term “saturated” in this case designates those radicals whichcontain no aliphatic multiple bonds, i.e. no ethylenic or acetylenicbonds.

Suitable compounds of the formula I which may be mentioned, for example,are

-   1-hydroxy-4-methyl-6-n-hexyl-, -6-iso-hexyl-, -6-n-heptyl- or    -6-isoheptyl-2-pyridone, 1-hydroxy-4-methyl-6-octyl- or    -6-isooctyl-2-pyridone, in particular as    1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone,    1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone,    1-hydroxy-4-methyl-6-cyclohexylmethyl- or    -6-cyclohexyl-ethyl-2-pyridone, where the cyclohexyl radical can in    each case also carry a methyl radical,    1-hydroxy-4-methyl-6-(2-bicyclo-[2.2.1]heptyl)-2-pyridone,    1-hydroxy-3,4-dimethyl-6-benzyl- or -6-dimethylbenzyl-2-pyridone and    1-hydroxy-4-methyl-6-(β-phenylethyl)-2-pyridone.

The invention furthermore relates to the use of the pharmaceuticalpreparation for the production of a pharmaceutical for the treatment andprophylaxis of dermatomycoses.

Using the pharmaceutical according to the invention, drastic healing canbe achieved in the treatment of dermatomycoses. The pharmaceuticalaccording to the invention is also suitable for prophylactic applicationagainst dermatomycoses.

The content of the compound of the formula I in the pharmaceuticalpreparation according to the invention is dependent on the structure ofeach compound of the formula I and thus on its release from the gel, itspenetration behavior in the skin and its antimicrobial properties.

In the pharmaceutical preparation according to the invention, thecompound of the formula I is in general contained in an amount from 0.05to 2 percent by weight, preferably 0.1 to 1% by weight.

Possible gel-forming agents are native substances such as gelatin,pectin, carrageenan, agar, tragacanth and alginates, semisyntheticgel-forming agents such as cellulose ethers (methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodiumcarboxymethyl-cellulose), starch derivatives, pectin derivatives, fullysynthetic gel-forming agents such as polyacrylates, polymethacrylates,polyvinyl alcohol, or mixtures thereof. Polyacrylates are particularlysuitable. These gel-forming agents are employed in amounts from 0.3 to2.0 parts by weight to 100 parts by weight of final product.

Suitable solvents are water and also all solvents miscible with water.Those suitable are, for example, alkanols such as ethanol or isopropylalcohol, and also propylene glycol and dimethyl sulfoxide. One or moresolvents can be employed in the preparation of the formulationsaccording to the invention.

Suitable additional solubilizers for the pharmaceutical preparationaccording to the invention are:

-   Benzyl alcohols, 2-octyldodecanol, adipates, propylene glycol and    glycerol. These solubilizers are contained in the preparations    according to the invention from 1 to 15 percent by weight (% by    weight).

Suitable further auxiliaries are emulsifiers, wetting agents andspreading agents.

The preparations are prepared in a manner known per se by combining theindividual components and—if necessary—further processing suited to theparticular preparation.

The present invention is explained in greater detail by the followingexamples, but is not restricted to these. If not stated otherwise, thequantitative data relate to the weight.

EXAMPLE 1

A preparation according to the invention has the following composition:

1-Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)pyridone 0.50%Hydroxyethylcellulose 1.50% Polyethylene glycol-7 glycerylcocoate 5.00%1,2-propane glycol 10.00% Isopropyl alcohol 20.00% Demineralized water63.00%

EXAMPLE 2

A preparation according to the invention has the following composition:

1-Hydroxy-4-methyl-6-cyclohexyl-2(1H)pyridone 1.00% Polyacrylic acidpolymer (e.g. Carbomer 934 P) 0.70% Sodium hydroxide 0.20% Sodiumdioctylsulfosuccinate 0.05% 2-octyldodecanol 7.50% Isopropyl alcohol25.00% Demineralized water 65.55%

EXAMPLE 3

A preparation according to the invention has the following composition:

1-Hydroxy-4-methyl-6-cyclohexyl-2(1H)pyridone 0.50% Polyacrylic acidpolymer (e.g. Carbomer 940) 0.50% Sodium hydroxide 0.20%Polyoxyethylene(20)sorbitan monostearate 3.50% Isopropyl myristate10.00% Ethanol 20.00% Demineralized water 65.30%

EXAMPLE 4

A preparation according to the invention has the following composition:

1-Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone 1.00%Hydroxypropylcellulose 1.00% 1,2-Propylene glycol 2.50% Ethanol 20.00%Demineralized water 75.50%

EXAMPLE 5

An ointment preparation from the prior art has the followingcomposition:

1-Hydroxy-4-methyl-6-cyclohexyl-2(1H)pyridone 1.00% Petroleum jelly20.00% Stearyl alcohol 15.00% 2-Octyldodecanol 10.00%Polyoxyethylene(20)sorbitan monostearate 3.50% Sorbitan monostearate1.50% Demineralized water 49.00%

EXAMPLE 6

Activity Testing

The active compound release of the pharmaceutical preparation accordingto the invention in a penetration model was tested using excised pig'sskin.

The testing of the active compound release from the compositionsaccording to the invention was carried out in a penetration model onexcised pig's skin. Here, a conclusion is drawn indirectly on the activecompound release from the compositions according to the invention viathe determination of the penetration depth by means of a microbiologicaldetermination method:

Relatively large pieces of back skin were excised from slaughtered pigsbefore scalding the killed animals. The back skin was wrapped with moistpaper and plastic film and deep frozen at −20° C. until the test.

Before the test, the skin surface was freed from fatty tissue, shavedand treated with isopropanol for 60 minutes for disinfection purposes.For each test batch a separate piece of skin (about 2×3 cm) was used.The skin surface was treated with preparations containing variouscompounds of formula I. After the end of the various action times (0.5,1 and 4 hours), the products were removed from the skin surface bywashing. In order to investigate the different penetration power of theactive compounds—or the different release power of the preparations—thepieces of skin were stripped off 2×, 6× and 10× using Scotch film on, ineach case, three adjacent tracks. Each track was then inoculated 10× ina punctiform manner with a suspension of Trichophyton mentagrophytes100/25 (about 200 microconidia per inoculation point). The pieces ofskin were then incubated at 28° C. for 7 days on water and agar withpenicillin, streptomycin and cycloheximide addition. From the 4th day ofincubation onwards, the result was daily read off macroscopically.

Results:

After a time of action of the active compound-containing gelpreparations, according to Examples 1 to 4, of 4 hours, the pieces ofskin are macroscopically fungus-free on all sections—in contrast to thecorresponding placebo preparations.

For the active compound-containing ointment preparation not according tothe invention, according to Example 5, which was prepared according tothe prior art, the time of action of 4 hours is not sufficient to killthe macroconidia on the inoculated segments.

1. A gel composition comprising: at least one compound chosen from1-hydroxy-4-methyl-6-cyclohexyl-2(1H)pyridone and physiologicallytolerable salts thereof; polyacrylic acid polymer; sodiumdioctylsulfosuccinate; and 2-octyldodecanol; wherein the composition isnot an emulsion.
 2. A gel composition comprising: at least one compoundchosen from 1-hydroxy-4-methyl-6-cyclohexyl-2(1H)pyridone andphysiologically tolerable salts thereof; polyacrylic acid polymer;polyoxyethylene(20)sorbitan monostearate; and isopropyl myristate;wherein the composition is not an emulsion.